DESCRIPTION The pro-inflammatory cytokine, interleukin-1 (IL-1), which is a key mediator of acute phase responses, activates, corticotropin- releasing factor (CRF)-expression neurons within the paraventricular nucleus (PVN). The goal of the proposed studies is to test the hypothesis that IL-1 induced activation of the PVN is dependent on a intramedullary prostaglandin-dependent signaling mechanism involving catecholaminergic cell groups that project to the PVN. In the first set of experiments, indomethacin, a prostaglandin synthesis inhibitor, will be microinjected into the Cl catecholamine cell group of the ventrolateral medulla of conscious rats to determine its efficacy in attenuating systemic IL-1 induced activation of the PVN, as assessed by the expression of the immediate-early gene (IEG), c-fos and CRF mRNA. Immunohistochemical and in situ hybridization techniques will be applied to determine the distribution of the main components of the proposed signaling cascade within the medulla. Specifically, the perivascular cell type(s) that express the type 1 IL-1 receptor and IL-1 induced cyclooxygenase and IEG expression will be analyzed. Similarly, it will be determined whether the EP3 prostaglandin E2 receptor is expressed by aminergic cells, themselves, or by local inhibitory interneurons. Finally, the generality of the proposed mechanism will be assessed by comparing the ability of neurotoxin lesions of ascending aminergic projections to interfere with PVN responses to graded doses of IL-1, or to a more potent and complex immune challenge presented by bacterial endotoxin. The results will test the validity and generality of a novel mechanism by which circulating cytokines come to discreetly influence brain systems involved in hypothalamo-pituitary- adrenal function, and thus cytokines come to discreetly influence brain systems involved in hypothalamo-pituitary-adrenal function, and thus begin to address clinically relevant problems associated with dysregulation of immune-neuroendocrine interactions.